This proposal will address gaps in our understanding of the intractable racial disparities in preterm birth and preeclampsia by exploring novel mechanisms underlying these pathways. We focus on maternal vitamin D, a previously unexplored candidate influence on pregnancy outcome. We have shown that vitamin D deficiency is pervasive among black women throughout pregnancy and is significantly less common among white women. Further, new data indicate that vitamin D has direct and indirect influences on inflammation and other known molecular pathways in the pathogenesis of spontaneous preterm birth (sPTB) and preeclampsia. Therefore, vitamin D status is an unexplored risk factor for sPTB and preeclampsia. The goal of this reproductive epidemiologic study is to elucidate the interplay between maternal vitamin D status, inflammation, and polymorphisms in genes involved in vitamin D metabolism on the risk of sPTB and preeclampsia. We will conduct complementary analyses in two racially- and geographically diverse multi-center U.S. prospective cohorts: the Collaborative Perinatal Project (n=55,908;46% white;47% black) and the NICHD Maternal-Fetal Medicine Units Network High-Risk Aspirin Study (n=917 pregnancies;33% white, 57% black). First, we aim to determine the independent association between maternal vitamin D status and the risk of sPTB and preeclampsia, and identify the extent to which this association is modified by maternal race. Vitamin D status at d26 weeks'gestation will be assessed using serum 25-hydroxyvitamin D. Second, we will evaluate the independent effect of maternal vitamin D status on maternal inflammation, and identify the extent to which this association is modified by maternal race. Maternal inflammation will be assessed using high-sensitivity C- reactive protein (CRP) measured at d26 weeks'gestation. Finally, we will determine the effect of maternal and fetal/neonatal genetic variation in key vitamin D metabolic loci on maternal vitamin D status, and on the risk of sPTB and preeclampsia. We will study genes whose protein products are directly involved in the metabolism of vitamin D: 25-hydroxylase (CYP27A1), 1a-hydroxylase (CYP27B1), vitamin D binding protein (GC), 24- hydroxylase (CYP24A1), vitamin D receptor (VDR), and retinoic acid receptor alpha (RARA). This project is highly responsive to the NIH Roadmap Initiative, given the confluence of expertise across epidemiologic, clinical, and biological sciences. Moreover, the project is significant because maternal vitamin D status is modifiable. Interventions to improve vitamin D status, such as a moderate increase in sunlight exposure or vitamin D supplementation, are inexpensive, safe, and acceptable to women. Given the high proportion of vitamin D inadequacy among black women, and the profound impact sPTB and preeclampsia have on perinatal morbidity, this project has tremendous capacity to benefit public health. PUBLIC HEALTH RELEVANCE: This proposal aims to explore the role of maternal vitamin D status during pregnancy as a risk factor for spontaneous preterm birth and preeclampsia, two adverse pregnancy outcomes that are associated with significant perinatal morbidity. The study hypotheses predict that vitamin D deficiency contributes to the racial disparity in spontaneous preterm birth and preeclampsia. Improving vitamin D status in pregnant women may be a simple strategy for reducing the excess cases of adverse birth outcomes among black women in the United States.